![]() ![]() The small size of the agent suggests that it might be able to replicate without nucleic acid, leading to the ‘prion’ hypothesis of an infectious polypeptide. However, several lines of evidence suggest that the prion theory is incomplete, and other data argue that a nucleic acid component may be obligatory for infection: first, the existence of multiple strains of the agent and the phenomenon of strain competition second, the paucity of infectivity of the recombinant prion protein, and third, evidence pointing directly to a nucleic acid component associated with the protein. The agent appears to be resistant to treatments that normally inactivate nucleic acids, and if a nucleic acid is associated with PrP, it has been argued to be short, excluding a conventional viral genome. In support, other than PrP itself, no other agent has been routinely detected in infectious fractions purified from diseased brain. (In the text we use the terms ‘protein-only’ and ‘prion’ theory interchangeably to refer to the concept that the infectious agent lacks an informational molecule such as a nucleic acid, but we do not exclude protein post-translational modifications and/or the presence of bound non-informational molecules such as lipids.) In turn, PrP Sc binds to PrP C and promotes Prp C → PrP Sc conversion, leading to amplification of (supposedly neurotoxic) PrP Sc and disease (see references for review). The ‘prion’ or ‘protein-only’ theory, as advocated by Prusiner and others (e.g., ), holds that the cellular form of the protein, PrP C, undergoes a conformation change, generating the ‘scrapie-specific’ form PrP Sc. Indeed, there has been little consensus about the physiological role of PrP, and its primary function has remained elusive. However, laboratory-raised Prnp-mutant mice display only subtle deficits, often irreproducible, in part because in four of six lines the knockout led to pathogenic upregulation of the adjacent Doppel ( Prnd) gene, explaining many discrepancies (reviewed in reference ). PrP has been ascribed multiple functions, ranging from synaptic plasticity to cell-surface signaling, cell–cell communication, and RNA metabolism (reviewed in references ). The detection of disease-specific amyloid-like plaques and fibrils was followed by the demonstration that these aggregates copurify with infectivity and, importantly, that a major component of these aggregates is a protease-resistant 27–30 kDa form of the host protein PrP, dubbed PrP Sc after the archetypal disease, scrapie, a refolded product of the native cellular precursor protein, PrP C, that is encoded by the PRNP gene in humans and by Prnp in mice. The archetypal features of TSEs, brain vacuolization and the presence of aggregated protein deposits, have been recognized for over a century (discussed in references ), although in some cases clinical disease can emerge in the absence of detectable proteinaceous aggregates (see below). Transmission of CJD to chimpanzees was later demonstrated by Gajdusek and colleagues (see also reference ). ![]() The transmissibility of scrapie by experimental inoculation was first demonstrated by Cuillé and Chelle, soon followed by transmission to goats and other species (reviewed in reference ). The socioeconomic impact of TSEs is illustrated by the BSE epidemic in 1990–1995, during which 4.4 million cattle were culled in the UK alone. TSEs are a group of neurodegenerative diseases that includes scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, transmissible mink encephalopathy, chronic wasting disease of elk and deer, and Creutzfeld–Jakob disease (CJD) in humans. The interested reader is referred to earlier reviews and opinions on the same topic (references and further references in the text). Although controversial, the notion that PrP associates with nucleic acids is of importance to explain the unusual properties of the infectious agent. Retroelement nucleic acids associated with PrP could underlie the different strains of TSEs that the protein-only theory fails to explain fully. The robust reverse transcription (RT) chaperoning activity of PrP and evidence that TSEs are accompanied by the mobilization of diverse retroviruses and retroelements suggest that TSE may involve retroelements. Starting with a brief overview of prion theory and its limitations, the biochemical properties of the PrP protein are revisited, notably the overlap between the nucleic-acid-binding/condensing, membrane-binding/inserting, and antiviral activities of PrP, which suggests that PrP and its processing products are antimicrobial proteins (AMPs). ![]() This paper aims to reconcile the existing data. A growing body of data suggests that the prion theory is incomplete and that the disease-specific form of the prion protein PrP deposited in TSE brain may not itself be the sole infectious villain. ![]()
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